Novel polymorphic forms of 5-[4-[2-[n-methyl-n-(2-pyridyl)amino[ethoxy]benzyl] thiazolidine-2,4-dione maleate and process for their preparation

ABSTRACT

This invention relates to novel polymorphic/pseudopolymorphic forms of 5-[4-[2[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl] thiazolidine-2,4-dione maleate having formula (I). The invention also relates to a pharmaceutical composition comprising the novel polymorphic form or their mixture and a pharmaceutically acceptable carrier. The polymorphic forms of the present invention are more active, as antidiabetic agent, than the hitherto known 5-[4-[2-[N-(2-methyl-N-(2-pyridyl)amino]ethoxy]benzyl] thiazolidine-2,4-dione maleate.

FIELD OF THE INVENTION

[0001] This invention relates to novel polymorphic/pseudopolymorphicforms of5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dionemaleate and its stereo- isomers having formula (I). The invention alsorelates to a pharmaceutical composition comprising the novel polymorphicform or their mixture and a pharmaceutically acceptable carrier. Thepolymorphic forms of the present invention are more active, asantidiabetic agent, than the hitherto known5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy] benzyl]thiazolidine-2,4-dione maleate.

[0002] The present invention also relates to a process for thepreparation of various polymorphic/pseudopolymorphic5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, having the formula (I) shownbelow. The polymorphic forms prepared by the process of the presentinvention are more active, as an antidiabetic agent.

[0003] The polymorphic forms of5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, of formula (I) defined above of thepresent invention reduce blood glucose and has beneficial effect oncoronary heart disease and atherosclerosis.

[0004] Out of the many drugs available for the treatment of diabeticailments, the thiazolidine dione derivatives are very prominent and areconsidered as much superior effective constituents compared to thesulphonyl ureas.5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dionemaleate, one such thiazolidinedione which exhibited euglycemic effect,was reported in the year 1988 by Beecham group England (EP 0306228A1)and created interest in the field, ever since.

[0005] The novel polymorphic forms of5-[4-[2-[N-methyl-N-2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dionemaleate, of formula (I) defined above of the present invention areuseful in reducing body weight and for the treatment and/or prophylaxisof diseases such as hypertension, coronary heart disease,atherosclerosis, stroke, peripheral vascular diseases and relateddisorders. The novel polymorphic forms of5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, of formula (I) ofthe present invention can be used for the treatment of certain renaldiseases including glomerulonephritis, glomerulosclerosis, nephroticsyndrome, hypertensive nephrosclerosis and nephropathy. The novelpolymorphic Forms of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, of formula (I) are also useful for thetreatment and/or prophylaxis of insulin resistance (type II diabetes),leptin resistance, impaired glucose tolerance, dyslipidemia, disordersrelated to syndrome X such as hypertension, obesity, insulin resistance,coronary heart disease and other cardiovascular disorders. These novelpolymorphic forms of5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dionemaleate, of formula (I) may also be useful as aldose reductaseinhibitors, for improving cognitive functions in dementia, treatingdiabetic complications, disorders related to endothelial cellactivation, psoriasis, polycystic ovarian syndrome (PCOS), inflammatorybowel diseases, osteoporosis, myotonic dystrophy, pancreatitis,arteriosclerosis, retinopathy, xanthoma, inflammation and for thetreatment of cancer. The novel polymorphic forms of5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, of formula (I) of the presentinvention are useful in the treatment and/or prophylaxis of the abovesaid diseases in combination/con-comittant with one or more HMG CoAreductase inhibitors, hypolipidemic/hypolipoproteinemic agents such asfibric acid derivatives, nicotinic acid, cholestyramine, colestipol,probucol.

BACKGROUND OF THE INVENTION

[0006] The latest trend that has, of late, crept into the pharmaceuticalindustry is the studies on polymorphism in drugs and the difference inthe activity of different polymorphic forms of a given drug. By the termpolymorphism we mean to include different physical forms, crystal forms,crystalline/liquid crystalline/non-crystalline (amorphous) forms. Thishas especially become very interesting after observing that manyantibiotics, antibacterials, tranquilizers etc., exhibit polymorphismand some/one of the polymorphic forms of a given drug exhibit superiorbio-availability and consequently show much higher activity compared toother polymorphs. Sertraline, Frentizole, Ranitidine, Sulfathiazole,Indomethacine etc. are some of the important examples of pharmaceuticalswhich exhibit polymorphism. Polymorphism in drugs is a topic of currentinterest and is evident from the host of patents being granted. To citea few, U.S. Pat. No. 5,700,820 discloses six polymorphic forms ofTroglitazone, U.S. Pat. No. 5,248,699 discusses about five polymorphicforms of Sertraline hydrochloride while EP 014590 describes fourpolymorphic forms of Frentizole. EP 490648 and EP 022527 also deal withthe subject of polymorphism in drugs.

[0007] European Patent No.0306338, International publication No. WO94/25026 and U.S. patent application Ser. No. 5,646,169 describe thatthe relative configurations of the diastereomers have been determined byx-ray crystallographic analysis and that the crystal and molecularstructure of the 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate is under preparation. The reportdoes not touch upon the possibility/observation that5-[4-[2-[N-methyl-N-(2-pyridyl)amino]thoxy]enzyl] thiazolidine-2,4-dionemaleate exists in different polymorphic forms. There is no publishedliterature regarding such an observation till date. Polymorphism indrugs is a topic of current interest and is evident from the host ofpatents being granted to cite a few U.S. Pat. No. 5,248,699 discussesabout five polymorphic forms of Sertraline hydrochloride while EP014590, describes four polymorphic forms of Frentizole EP 490648 and EP022527, six polymorphic forms of Troglitazone WO 97/27191 also deal withthe subject of polymorphism in drugs. The fact that polymorphism in5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate has not been studiedearlier coupled with the current interest in the field of polymorphismin drugs prompted us to take-up this investigation our observations andresults from the subject matter of the present invention.

[0008] With a view to prevent/cure the chronic complications ofdiabetes, research is being conducted round the world in recent times.5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate is being considered todayas one of the most effective anti-diabetic drugs which as amulti-purpose activity not only acting on diabetes itself but also onthe reduction of the triglycerides and also on the accompanyingcomplications mentioned above. Indeed the said5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate is emerging as the seconddrug candidate of euglycemic class of antidiabetic agents.

[0009] With an objective to develop novel polymorphic forms for loweringcholesterol and reducing body weight with beneficial effects in thetreatment and/or prophylaxis of diseases related to increased levels oflipids, atherosclerosis, coronary artery diseases, Syndrome-X, impairedglucose tolerance, insulin resistance, insulin resistance leading totype 2 diabetes and diabetes complications thereof, for the treatment ofdiseases wherein insulin resistance is the pathophysiological mechanismand for the treatment of hypertension, with better efficacy, potency andlower toxicity, we focused our research to develop new polymorphic formseffective in the treatment of the above mentioned diseases. Effort inthis direction has led to polymorphic forms having the formula (I).

[0010] Another objective of the present invention is to providepolymorphic forms of5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dionemaleate, their stereoisomers, their pharmaceutically acceptable solvatesand pharmaceutical compositions containing them or their mixtures whichmay have agonist activity against PPARα and/or PPARγ, and optionallyinhibit HMG CoA reductase, in addition to having agonist activityagainst PPARα and/or PPARγ.

[0011] Another objective of the present invention is to provide novelpolymorphic forms of5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dionemaleate, their stereoisomers, pharmaceutically acceptable solvates andpharmaceutical compositions containing them or their mixtures havingenhanced activities, without toxic effect or with reduced toxic effect.

[0012] Yet another objective of the present invention to provide aprocess for the preparation of novel polymorphic forms of5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, their stereoisomers,pharmaceutically acceptable solvates.

[0013] Still another objective of the present invention is to providepharmaceutical compositions containing novel polymorphic forms of5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, solvates or theirmixtures in combination with suitable carriers, solvents, diluents andother media normally employed in preparing such compositions.

SUMMARY OF THE INVENTION

[0014] The present invention relates to an observation that5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dionemaleate exhibits polymorphism, which has not been reported till date.The polymorphic Forms I, II, III and IV are obtained from differentsolvents like ethanol, acetone, methanol and 1,4-dioxane respectively.

[0015] From powder X-ray diffraction studies Forms I, II, III and IV arefound to be crystalline in nature.

[0016] DSC of the polymorphic Form I shows melting endotherm at 100.53°C. Form II dislays endotherm at 127.67° C. Form m exhibits meltingendotherm at 126.41° C. and Form IV exhibits endotherm at 125.39° C.

[0017] All these polymorphic forms were proved to be identical insolution as evident from Nuclear Magnetic Resonance (NMR), Ultra Violet(UV) & Mass spectral data. On the other hand, solid state techniqueslike Differential Scanning Calorimetry (DSC), Powder X-RayDiffractometry (XRD) and Infra Red spectroscopy (IR) revealed thedifference among these forms.

BRIEF DESCRIPTION OF THE FIGURES

[0018] X-ray powder diffraction pattern has been obtained on a RigakuD/Max 2200 model diffractometer equiped with horizontal gonimometer inΘ/2 Θ geometry. The copper K α(λ=1.5418A) radiation was used and thesample was scanned between 3-45 degrees 2Θ.

[0019] Differential scanning calorimeter was performed on a ShimadzuDSC-50 equipped with a controller. The data was collected on to aPentium PC using a Shimadzu TA-50 software. The samples weighed inaluminum cells were heated from room temperature to 220° C. at a heatingrate of 5° C./min. The empty aluminum cell was used as a reference. Drynitrogen gas was purged through DSC cell continuously throughout theanalysis at a flow rate of 30 ml/min.

[0020]FIG. 1 is a characteristic differential scanning calorimetricthermogram of Form I

[0021]FIG. 2 is a characteristic differential scanning calorimetricthermogram of Form II

[0022]FIG. 3 is a characteristic differential scanning calorimetricthermogram of Form III

[0023]FIG. 4 is a characteristic differential scanning calorimetricthermogram of Form IV

[0024]FIG. 5 is a characteristic X-ray diffraction pattern of Form I

[0025]FIG. 6 is a characteristic X-ray diffraction pattern of Form II

[0026]FIG. 7 is a characteristic X-ray diffraction pattern of Form III

[0027]FIG. 8 is a characteristic X-ray diffraction pattern of Form IV

[0028]FIG. 9 is the multi-plot of X-ray diffraction patterns of Forms I,II, III and IV

[0029]FIG. 10 is a characteristic infrared absorption spectrum of Form Iin potassium bromide.

[0030]FIG. 11 is a characteristic infrared absorption spectrum of FormII in potassium bromide.

[0031]FIG. 12 is a characteristic infrared absorption spectrum of FormIII in potassium bromide.

[0032]FIG. 13 is a characteristic infrared absorption spectrum of FormIV in potassium bromide.

DETAILED DESCRIPTION OF THE INVENTION

[0033] According to a feature of the present invention, there isprovided a novel polymorphic Form-I of5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, and its stereoisomers having the formulaI which is characterized by the following data:

[0034] DSC endotherm at 100.53° C. (on set at 88.65° C.) (FIG. 1).

[0035] X Ray powder diffraction (2Θ): 10.90, 14.54, 15.96, 18.46, 18.60,19.76, 20.72, 21.84, 22.36, 22,46, 23.90, 24.04, 24.72, 25.30, 25.98,27.44, 29.70 (FIG. 5).

[0036] IR (cm⁻): 3435 (m), 2997 (w), 2773 (m), 1750 (m), 1701 (s), 1620(m), 1510 (m), 1362 (m), 1332 (m), 1237 (s), 1165 (m), 864 (s), 764 (s),717 (m), 654 (m), 540 (w), FIG. (10).

[0037] According to another feature of the present invention, there isprovided a novel polymorphic Form-II of5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, and its stereoisomers having the formulaI which is characterized by the following data:

[0038] DSC: Endotherm at 127.67° C. (on set at 123.17° C.) FIG. 2.

[0039] XRD (2Θ): 8.90, 15.40, 18.06, 19.20, 22.30, 23.40, 23.62, 24.80,25.10, 25.84, 26.72, 27.18, 29.30, 29.54, 29.84, 33.26 (FIG. 6).

[0040] IR: 3424 (w), 3040 (w), 2947 (m), 2720 (m), 1751 (m), 1702 (s),1641 (m), 1618 (m), 1574 (w), 1541 (w), 1412 (w), 1382 (w), 1359 (m),1326 (m), 1265 (w), 1242 (s), 1213 (w), 1162 (s), 1067 (w), 1031 (w),865 (s), 773 (s), 713 (s), 667 (m), 576 (w), 539 (m), (FIG. 11).

[0041] According to yet another feature of the present invention, thereis provided a novel polymorphic Form-III of5-[4-[2-[N-methyl-N-2-pyridyl)amino] ethoxy]benzyl]thiazolidine-2,4-dione maleate and its stereoisomers having the formulaI which is characterized by the following data:

[0042] DSC: Endotherm at 126.41° C. (on set at 122.06° C.) (FIG. 3).

[0043] XRD (2Θ): 4.60, 8.46, 9.24, 14.98, 15.86, 17.02, 18.60, 21.92,23.50, 25.00, 25.44, 26.00, 26.38, 28.34, 33.90 (FIG. 7).

[0044] IR: 3429 (m), 2949 (m), 2738 (m), 1747 (w), 1704 (s), 1641 (m),1617 (m), 1513 (s), 1464 (m), 1352 (m), 1244 (s), 1178 (s), 1069 (m),862 (w), 777 (s), 717 (m), 657 (m), 589 (w) (FIG. 12).

[0045] According to yet another feature of the present invention, thereis provided a novel polymorphic Form-IV of5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, and its stereoisomers having the formulaI which is characterized by the following data:

[0046] DSC: Endotherm at 125.39° C. (on set at 121.03° C.) (FIG. 4).

[0047] XRD (2Θ): 7.4, 8.8, 9.54, 14.98, 15.32, 15.82, 16.90, 17.70,18.40, 18.54, 19.08, 19.72, 20.22, 20.48, 21.36, 21,66, 22.18, 22.58,23.32, 23.96, 24.52, 25.38, 26.48, 27.00, 27.58, 27.94, 28.34, 28.54,28.84, 29.10, 29.86, 30.02, 30.40, 30.52, 30.84, 31.40, 31.94 (FIG. 8).

[0048] IR: 3433 (m), 2930 (m), 1753 (w), 1705 (s), 1642 (w), 1617 (m),1512 (s), 1467 (w), 1351 (m), 1244 (m), 1162 (m), 1061 (w), 864 (s), 765(s), 714 (w), 658 (m), 526 (w) (FIG. 13).

[0049] According to another feature of the present invention, there isprovided a process for the preparation of novel polymorphic Form-I of5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, of the formula I,having the characteristics described earlier, which comprises:

[0050] (i) synthesizing5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, employing known methods and dissolvingin ethanol,

[0051] (ii) heating the solution in a steam bath till the solidcompletely dissolved,

[0052] (iii) filtering the clear solution and cooling to roomtemperature over a period of 18 h,

[0053] (iv) isolating the Form I of5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate formed.

[0054] According to another feature of the present invention, there isprovided a process for the preparation of novel polymorphic Form-II of5-[4-[2-[N-methyl-N-2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, of the formula I, havingthe characteristics described earlier, which comprises:

[0055] (i) synthesizing5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, employing known methods and dissolvingin acetone,

[0056] (ii) heating the solution in a steam bath till the solidcompletely dissolved,

[0057] (iii) filtering the clear solution and cooling to roomtemperature over a period of 18 h,

[0058] (iv) isolating the Form II of5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate formed.

[0059] According to another feature of the present invention, there isprovided a process for the preparation of novel polymorphic Form-III of5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, of the formula I, havingthe characteristics described earlier, which comprises:

[0060] (i) synthesizing5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl] thiazolidine-2,4-dione maleate, employing known methods and dissolving in methanol,

[0061] (ii) heating the solution in a steam bath till the solidcompletely dissolved,

[0062] (iii) filtering the clear solution and cooling to roomtemperature over a period of 18 h,

[0063] (iv) isolating the Form m of5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate formed.

[0064] According to yet another feature of the present invention, thereis provided a process for the preparation of novel polymorphic Form-IVof 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate of the formula I, havingthe characteristics described earlier, which comprises:

[0065] (i) synthesizing5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, employing known methods and dissolvingin 1,4-dioxane,

[0066] (ii) heating the solution in a steam bath till the solidcompletely dissolved,

[0067] (iii) filtering the clean solution and cooling to roomtemperature over a period of 18 h,

[0068] (iv) isolating the Form IV of5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate formed.

[0069] The stereoisomers of the compounds forming part of this inventionmay be prepared by using reactants in their single enantiomeric form inthe process wherever possible or by conducting the reaction in thepresence of reagents or catalysts in their single enantiomer form or byresolving the mixture of stereoisomers by conventional methods. Some ofthe preferred methods include use of microbial resolution, resolving thediastereomeric salts formed with chiral acids such as mandelic acid,camphorsulfonic acid, tartaric acid, lactic acid, and the like whereverapplicable or chiral bases such as brucine, cinchona alkaloids and theirderivatives and the like. Commonly used methods are compiled by Jaqueset al in “Enantiomers, Racemates and Resolution” (Wiley Interscience,1981. Conventional reaction conditions may be employed to convert acidinto an amide; the diastereomers may be separated either by fractionalcrystallization or chromatography and the stereoisomers of compound offormula (I) may be prepared by hydrolyzing the pure diastereomericamide.

[0070] The present invention also envisages a pharmaceutical compositioncomprising any of the polymorphic Forms I to IV of5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy] benzyl]thiazolidine-2,4-dione maleate, of the formula (I) and apharmaceutically acceptable carrier.

[0071] The present invention also envisages a pharmaceutical compositioncomprising a mixture of any of polymorphic Forms I to IV of5-[4-[2-[N-methyl-N-(2-pyridyl) amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, of the formula (I) and apharmaceutically acceptable carrier.

[0072] The pharmaceutical composition may be in the forms normallyemployed, such as tablets, capsules, powders, syrups, solutions,suspensions and the like, may contain flavourants, sweeteners etc. insuitable solid or liquid carriers or diluents, or in suitable sterilemedia to form injectable solutions or suspensions. Such compositionstypically contain from 1 to 25%, preferably 1 to 15% by weight of activeingredient, the remainder of the composition being pharmaceuticallyacceptable carriers, diluents or solvents.

[0073] The polymorphic forms of the formula (I) as defined above areclinically administered to mammals, including man, via either oral,nasal, pulmonary, transdermal or parenteral rectal, depot, subcutaneous,intravenous, intraurethral, intramuscular, intranasal, ophthalmicsolution or an ointment. Administration by the oral route is preferred,being more convenient and avoiding the possible pain and irritation ofinjection. However, in circumstances where the patient cannot swallowthe medication, or absorption following oral administration is impaired,as by disease or other abnormality, it is essential that the drug beadministered parenterally. By either route, the dosage is in the rangeof about 0.01 to about 100 mg/kg body weight of the subject per day orpreferably about 0.01 to about 30 mg/kg body weight per day administeredsingly or as a divided dose. However, the optimum dosage for theindividual subject being treated will be determined by the personresponsible for treatment, generally smaller doses being administeredinitially and thereafter increments made to determine the most suitabledosage.

[0074] Suitable pharmaceutically acceptable carriers include solidfillers or diluents and sterile aqueous or organic solutions. The activeingredient will be present in such pharmaceutical compositions in theamounts sufficient to provide the desired dosage in the range asdescribed above. Thus, for oral administration, the polymorphic form canbe combined with a suitable solid or liquid carrier or diluent to formcapsules, tablets, powders, syrups, solutions, suspensions and the like.The pharmaceutical compositions, may, if desired, contain additionalcomponents such as flavourants, sweeteners, excipients and the like. Forparenteral administration, the polymorphic form can be combined withsterile aqueous or organic media to form injectable solutions orsuspensions. For example, solutions in sesame or peanut oil, aqueouspropylene glycol and the like can be used, as well as aqueous solutionsof water-soluble pharmaceutically-acceptable acid addition salts orsalts with base of the compounds. Aqueous solutions with the activeingredient dissolved in polyhydroxylated castor oil may also be used forinjectable solutions. The injectable solutions prepared in this mannercan then be administered intravenously, intraperitoneally,subcutaneously, or intramuscularly, with intramuscular administrationbeing preferred in humans.

[0075] For nasal administration, the preparation may contain thepolymorphic forms of the present invention dissolved or suspended in aliquid carrier, in particular an aqueous carrier, for aerosolapplication. The carrier may contain additives such as solubilizingagents, such as propylene glycol, surfactants, absorption enhancers suchas lecithin (phosphatidylcholine) or cyclodextrin or preservatives suchas parabenes.

[0076] Tablets, dragees or capsules having talc and/or a carbohydratecarried binder or the like are particularly suitable for any oralapplication. Preferably, carriers for tablets, dragees or capsulesinclude lactose, corn starch and/or potato starch. A syrup or elixir canbe used in cases where a sweetened vehicle can be employed.

[0077] A typical tablet production method is exemplified below:

[0078] Tablet Production Example: a) 1) Active ingredient  30 g 2)Lactose  95 g 3) Corn starch  30 g 4) Carboxymethyl cellulose  44 g 5)Magnesium stearate  1 g 200 g for 1000 tablets

[0079] The ingredients 1 to 3 are uniformly blended with water andgranulated after drying under reduced pressure. The ingredient 4 and 5are mixed well with the granules and compressed by a tabletting machineto prepare 1000 tablets each containing 30 mg of active ingredient.b) 1) Active ingredient  30 g 2) Calcium phosphate  90 g 3) Lactose  40g 4) Corn starch  35 g 5) Polyvinyl pyrrolidone  3.5 g 6) Magnesiumstearate  1.5 g 200 g for 1000 tablets

[0080] The ingredients 14 are uniformly moistened with an aqueoussolution of 5 and granulated after drying under reduced pressure.Ingredient 6 is added and granules are compressed by a tablettingmachine to prepare 1000 tablets contining 30 mg of ingredient 1.

[0081] The present invention is described in detail in the examplesgiven below which are provided by way of illustration only and thereforeshould not be construed to limit the scope of the invention.

EXAMPLES Example-1

[0082] A mixture of5-[4-[2-[N-methyl-N-2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione(69 g, 0.19 M) and maleic acid (22.8 g, 0.19 M) was heated under refluxwhile stirring in iso-propanol (1.0 L) until a clear solution wasobtained (1-2 h). The reaction mass was allowed to cool to RT whilestirring for 15-20 h. The white to off-white crystalline compound wasfiltered, washed with iso-propanol (3×100 ml) and pet. ether (2×100 ml)dried to furnish white to off-white product (84.5 g; Yield: 92%).

Example 2

[0083] 1 g of the5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dionemaleate obtained by the process as described in Example-1 was taken in10 ml EtOH and heated on a steam bath till the solid completelydissolved. The clear solution was allowed to cool to RT over a period of18 h to yield 80% of >99% pure polymorphic Form I of5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dionemaleate.

Example 3

[0084] 1 g of the5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dionemaleate obtained by the process as described in Example-1 was taken in50 ml acetone and heated on a steam bath till the solid completelydissolved. The solution was allowed to cool to RT over a period of 18 hto yield 60% of >99% pure polymorphic Form II of5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dionemaleate.

Example 4

[0085] 1 g of the5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dionemaleate obtained by the process as described in Example-1 was dissolvedin 10 ml of methanol and heated on a steam bath till the solidcompletely dissolved. The clear solution was filtered and allowed tocool to RT over a period of 18 h to yield 75% of >99% pure polymorphicForm III of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy] benzyl]thiazolidine-2,4-dione maleate.

Example 5

[0086] 1 g of the5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazoidine-2,4-dionemaleate obtained by the process as described in Example-1 was taken in10 ml 1,4-dioxane and heated on a steam bath till the solid completelydissolved. The clear solution was allowed to cool to RT over a period of18 h to yield 70% of >99% pure polymorphic Form IV of5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dionemaleate.

1. A novel polymorphic Form-I of 5-[4-[2-[N-methyl-N-(2-pyridyl) amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, and its stereoisomershaving the formula I

which is characterized by the following data: DSC endotherm at 100.53°C. (on set at 88.65° C.), X Ray powder diffraction (2Θ): 10.90, 14.54,15.96, 18.46, 18.60, 19.76, 20.72, 21.84, 22.36, 22,46, 23.90, 24.04,24.72, 25.30, 25.98, 27.44, 29.70, Ir (cm⁻¹): 3435 (m), 2997 (w), 2773(m), 1750 (m), 1701 (s), 1620 (m), 1510 (m), 1362 (m), 1332 (m), 1237(s), 1165 (m), 864 (s), 764 (s), 717 (m), 654 (m), 540 (w).
 2. A novelpolymorphic Form-II of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, and its stereoisomershaving the formula I

which is characterized by the following data: DSC: Endotherm at 127.67°C. (on set at 123.17° C.), XRD (2Θ): 8.90, 15.40, 18.06, 19.20, 22.30,23.40, 23.62, 24.80, 25.10, 25.84, 26.72, 27.18, 29.30, 29.54, 29.84,33.26, IR: 3424 (w), 3040 (w), 2947 (m), 2720 (m), 1751 (m), 1702 (s),1641 (m), 1618 (m), 1574 (w), 1541 (w), 1412 (w), 1382 (w), 1359 (m),1326 (m), 1265 (w), 1242 (s), 1213 (w), 1162 (s), 1067 (w), 1031 (w),865 (s), 773 (s), 713 (s), 667 (m), 576 (w), 539 (m).
 3. A novelpolymorphic Form-III of5-[4-[2-[N-methyl-N-2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dionemaleate and its stereoisomers having the formula I

which is characterized by the following data: DSC: Endotherm at 126.41°C. (on set at 122.06° C.), XRD (2Θ): 4.60, 8.46, 9.24, 14.98, 15.86,17.02, 18.60, 21.92, 23.50, 25.00, 25.44, 26.00, 26.38, 28.34, 33.90,IR: 3429 (m), 2949 (m), 2738 (m), 1747 (w), 1704 (s), 1641 (m), 1617(m), 1513 (s), 1464 (m), 1352 (m), 1244 (s), 1178 (s), 1069 (m), 862(w), 777 (s), 717 (m), 657 (m), 589 (w).
 4. A novel polymorphic Form-IVof 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, and its stereoisomershaving the formula I

which is characterized by the following data: DSC: Endotherm at 125.39°C. (on set at 121.03° C.), XRD (2Θ): 7.4, 8.8, 9.54, 14.98, 15.32,15.82, 16.90, 17.70, 18.40, 18.54, 19.08, 19.72, 20.22, 20.48, 21.36,21,66, 22.18, 22.58, 23.32, 23.96, 24.52, 25.38, 26.48, 27.00, 27.58,27.94, 28.34, 28.54, 28.84, 29.10, 29.86, 30.02, 30.40, 30.52, 30.84,31.40, 31.94, IR: 3433 (m), 2930 (m), 1753 (w), 1705 (s), 1642 (w), 1617(m), 1512 (s), 1467 (w), 1351 (m), 1244 (m), 1162 (m), 1061 (w), 864(s), 765 (s), 714 (w), 658 (m), 526 (w).
 5. A process for thepreparation of novel polymorphic Form I of5-[4-[2-[N-methyl-N-2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dionemaleate, which comprises (i) synthesizing5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, employing known methods and dissolvingin ethanol (ii) heating the solution in a steam bath till the solidcompletely dissolved, (iii) filtering the clean solution and cooling toroom temperature over a period of 18 h and (iv) isolating the Form I of5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate formed.
 6. A process for thepreparation of novel polymorphic Form II of5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dionemaleate, which comprises: (i) synthesizing5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, employing known methods and dissolvingin acetone, (ii) heating the solution in a steam bath till the solidcompletely dissolved, (iii) filtering the clean solution and cooling toroom temperature over a period of 18 h and (iv) isolating the Form II of5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate formed.
 7. A process for thepreparation of novel polymorphic Form III of5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dionemaleate, which comprises: (i) synthesizing5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, employing known methods and dissolvingin methanol, (ii) heating the solution in a steam bath till the solidcompletely dissolved, (iii) filtering the clean solution and cooling toroom temperature over a period of 18 h and (iv) isolating the Form IIIof 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-ione maleate formed.
 8. A process for thepreparation of novel polymorphic Form IV of5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dionemaleate, which comprises: (i) synthesizing5-[4-[2-[N-methyl-N-2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, employing known methods and dissolvingin 1,4-dioxane, (ii) heating the solution in a steam bath till the solidcompletely dissolved, (iii) filtering the clean solution and cooling toroom temperature over a period of 18 h and (iv) isolating the Form IV of5-[4-[2-[N-methyl-N-2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate formed.
 9. A pharmaceuticalcomposition comprising a mixture of any of polymorphic Forms I to IV of5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, of the formula (I) and apharmaceutically acceptable carrier, diluent, excipient or solvate. 10.A pharmaceutical composition as claimed in claim 9, in the form of atablet, capsule, powder, syrup, solution or suspension.
 11. A method ofpreventing or treating hyperlipemia, hypercholesteremia, hyperglycemia,osteoporosis, obesity, glucose intolerance, leptin resistance, insulinresistance, or diseases in which insulin resistance is the underlyingpathophysiological mechanism comprising administering a polymorphic Formselected from Form I to IV of5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dionemaleate, having the formula I as defined in claims 1-4 or apharmaceutical composition as claimed in claims 9 and 10 to a patient inneed thereof.
 12. A method according to claim 11, wherein the disease istype II diabetes, impaired glucose tolerance, dyslipidaemia, disordersrelated to Syndrome X such as hypertension, obesity, atherosclerosis,hyperlipidemia, coronary artery disease and other cardiovasculardisorders, certain renal diseases including glomerulonephritis,glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis,retinopathy, nephropathy, disorders related to endothelial cellactivation, psoriasis, polycystic ovarian syndrome (PCOS), useful asaldose reductase inhibitors, for improving cognitive functions indementia and treating diabetic complications, osteoporosis, inflammatorybowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis,xanthoma and cancer.
 13. A method of reducing plasma glucose,triglycerides, total cholesterol, LDL, VLDL and free fatty acids in theplasma comprising administering a polymorphic Form selected from Form Ito IV of 5-[4-[2-[N-methyl-N-2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, having the formula I as defined inclaims 1-4 or a pharmaceutical composition as claimed in claims 9 and10.
 14. A method of preventing or treating hyperlipemia,hypercholesteremia, hyperglycemia, osteoporosis, obesity, glucoseintolerance, leptin resistance, insulin resistance, or diseases in whichinsulin resistance is the underlying pathophysiological mechanismcomprising administering a polymorphic Form selected from Form I to IVof5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazoolidine-2,4-dionemaleate, having the formula I as defined in claims 1-4 or apharmaceutical composition as claimed in claims 9 and 10 incombination/concomittant with HMG CoA reductase inhibitors or fibratesor nicotinic acid or cholestyramine or colestipol or probucol which maybe administered together or within such a period as to actsynergistically together to a patient in need thereof.
 15. A methodaccording to claim 14, wherein the disease is type II diabetes, impairedglucose tolerance, dyslipidaemia, disorders related to Syndrome X suchas hypertension, obesity, atherosclerosis, hyperlipidemia, coronaryartery disease and other cardiovascular disorders, certain renaldiseases including glomerulonephritis, glomerulosclerosis, nephroticsyndrome, hypertensive nephrosclerosis, retinopathy, nephropathy,disorders related to endothelial cell activation, psoriasis, polycysticovarian syndrome (PCOS), useful as aldose reductase inhibitors, forimproving cognitive functions in dementia and treating diabeticcomplications, osteoporosis, inflammatory bowel diseases, myotonicdystrophy, pancreatitis, arteriosclerosis, xanthoma and cancer.
 16. Amethod according to claim 14 for the treatment and/or prophylaxis ofdisorders related to Syndrome X, which comprises administering apolymorphic Form selected from Form I to IV of5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, having the formula I as defined inclaims 1-4 in combination with HMG CoA reductase inhibitors or fibratesor nicotinic acid or cholestyramine or colestipol or probucol which maybe administered together or within such a period as to actsynergistically together.
 17. A method of reducing plasma glucose,triglycerides, total cholesterol, LDL, VLDL and free fatty acids in theplasma, which comprises administering a polymorphic Form selected fromForm I to IV of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, having the formula I as definedin claims 1-4 or a pharmaceutical composition as claimed in claims 9 and10 in combination/concomittant with HMG CoA reductase inhibitors orfibrates or nicotinic acid or cholestyramine or colestipol or probucolwhich may be administered together or within such a period as to actsynergistically together to a patient in need thereof.
 18. Use of apolymorphic Form selected from Form I to IV of5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dionemaleate, having the formula I as defined in claims 1-4 or apharmaceutical composition as claimed in claims 9 and 10 for preventingor treating hyperlipidemia, hypercholesteremia, hyperglycemia,osteoporosis, obesity, glucose intolerance, leptin resistance, insulinresistance, or diseases in which insulin resistance is the underlyingpathophysiological mechanism.
 19. Use of a polymorphic Form according toclaim 18, wherein the disease is type II diabetes, impaired glucosetolerance, dyslipidaemia, disorders related to Syndrome X such ashypertension, obesity, atherosclerosis, hyperlipidemia, coronary arterydisease and other cardiovascular disorders, certain renal diseasesincluding glomerulonephritis, glomerulosclerosis, nephrotic syndrome,hypertensive nephrosclerosis, retinopathy, nephropathy, disordersrelated to endothelial cell activation, psoriasis, polycystic ovariansyndrome (PCOS), useful as aldose reductase inhibitors, for improvingcognitive functions in dementia and treating diabetic complications,osteoporosis, inflammatory bowel diseases, myotonic dystrophy,pancreatitis, arteriosclerosis, xanthoma or cancer.
 20. Use of apolymorphic Form selected from Form I to IV of5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dionemaleate, having the formula I as defined in claims 1-4 or apharmaceutical composition as claimed in claims 9 and 10 for reducingplasma glucose, triglycerides, total cholesterol, LDL, VLDL and freefatty acids in the plasma.
 21. Use of a polymorphic Form selected fromForm I to IV of5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dionemaleate, having the formula I as defined in claims 1-4 or apharmaceutical composition as claimed in claims 9 and 10 incombination/concomittant with HMG CoA reductase inhibitors, fibrates,nicotinic acid, cholestyramine, colestipol or probucol which may beadministered together or within such a period as to act synergisticallytogether for preventing or treating hyperlipidemia, hypercholesteremia,hyperglycemia, osteoporosis, obesity, glucose intolerance, leptinresistance, insulin resistance, or diseases in which insulin resistanceis the underlying pathophysiological mechanism to a patient in needthereof.
 22. Use of a polymorphic Form according to claim 21, whereinthe disease is type II diabetes, impaired glucose tolerance,dyslipidaemia, disorders related to Syndrome X such as hypertension,obesity, atherosclerosis, hyperlipidemia, coronary artery disease andother cardiovascular disorders, certain renal diseases includingglomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensivenephrosclerosis, retinopathy, nephropathy, disorders related toendothelial cell activation, psoriasis, polycystic ovarian syndrome(PCOS), useful as aldose reductase inhibitors, for improving cognitivefunctions in dementia and treating diabetic complications, osteoporosis,inflammatory bowel diseases, myotonic dystrophy, pancreatitis,arteriosclerosis, xanthoma or cancer.
 23. Use of a polymorphic Formselected from Form I to IV of5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dionemaleate, having the formula I as defined in claims 1-4 or apharmaceutical composition as claimed in claims 9 and 10 incombination/concomittant with HMG CoA reductase inhibitors, fibrates,nicotinic acid, cholestyramine, colestipol or probucol for reducingplasma glucose, triglycerides, total cholesterol, LDL, VLDL or freefatty acids in the plasma.
 24. Use of a polymorphic Form selected fromForm I to IV of5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dionemaleate, having the formula I as defined in claims 1-4 or apharmaceutical composition as claimed in claims 9 and 10 for preparing amedicament for preventing or treating hyperlipidemia,hypercholesteremia, hyperglycemia, osteoporosis, obesity, glucoseintolerance, leptin resistance, insulin resistance, or diseases in whichinsulin resistance is the underlying pathophysiological mechanism. 25.Use of a polymorphic form according to claim 24, wherein the disease istype II diabetes, impaired glucose tolerance, dyslipidaemia, disordersrelated to Syndrome X such as hyper-tension, obesity, atherosclerosis,hyperlipidemia, coronary artery disease and other cardiovasculardisorders, certain renal diseases including glomerulonephritis,glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis,retinopathy, nephropathy, disorders related to endothelial cellactivation, psoriasis, polycystic ovarian syndrome (PCOS), useful asaldose reductase inhibitors, for improving cognitive functions indementia and treating diabetic complications, osteoporosis, inflammatorybowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis,xanthoma or cancer.
 26. Use of a polymorphic Form selected from Form Ito IV of5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dionemaleate, having the formula I as defined in claims 1-4 or apharmaceutical composition as claimed in claims 9 and 10 for preparing amedicament for reducing plasma glucose, triglycerides, totalcholesterol, LDL, VLDL and free fatty acids in the plasma
 27. Use of apolymorphic Form selected from Form I to IV of5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dionemaleate, having the formula I as defined in claims 1-4 or apharmaceutical composition as claimed in claims 9 and 10 for preparing amedicament in combination/concomittant with EMG CoA reductaseinhibitors, fibrates, nicotinic acid, cholestyramine, colestipol orprobucol for preventing or treating hyperlipermia, hypercholesteremia,hyperglycemia, osteoporosis, obesity, glucose intolerance, leptinresistance, insulin resistance, or diseases in which insulin resistanceis the underlying pathophysiological mechanism.
 28. Use of a polymorphicform according to claim 27, wherein the disease is type II diabetes,impaired glucose tolerance, dyslipidaemia, disorders related to SyndromeX such as hypertension, obesity, atherosclerosis, hyperlipidemia,coronary artery disease and other cardiovascular disorders, certainrenal diseases including glomerulonephritis, glomerulosclerosis,nephrotic syndrome, hypertensive nephrosclerosis, retinopathy,nephropathy, disorders related to endothelial cell activation,psoriasis, polycystic ovarian syndrome (PCOS), useful as aldosereductase inhibitors, for improving cognitive functions in dementia andtreating diabetic complications, osteoporosis, inflammatory boweldiseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthomaor cancer.
 29. Use of a polymorphic Form selected from Form I to IV of5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dionemaleate, having the formula I as defined in claims 1-4 or apharmaceutical composition as claimed in claims 9 and 10 for preparing amedicament in combination/concomittant with HMG CoA reductaseinhibitors, fibrates, nicotinic acid, cholestyramine, colestipol orprobucol for reducing plasma glucose, triglycerides, total cholesterol,LDL, VLDL or free fatty acids in the plasma.
 30. A medicine forpreventing or treating hyperlipidemia, hypercholesteremia,hyperglycemia, osteoporosis, obesity, glucose intolerance, leptinresistance, insulin resistance, or diseases in which insulin resistanceis the underlying pathophysiological mechanism comprising administeringan effective amount of a polymorphic Form selected from Form I to IV of5-[4-[2-[N-methyl-N-2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, having the formula I as definedin claims 1-4 or a pharmaceutical composition as claimed in claims 9 and10.
 31. A medicine according to claim 30, wherein the disease is type IIdiabetes, impaired glucose tolerance, dyslipidaemia, disorders relatedto Syndrome X such as hypertension, obesity, atherosclerosis,hyperlipidemia, coronary artery disease and other cardiovasculardisorders, certain renal diseases including glomerulonephritis,glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis,retinopathy, nephropathy, disorders related to endothelial cellactivation, psoriasis, polycystic ovarian syndrome (PCOS), useful asaldose reductase inhibitors, for improving cognitive functions indementia and treating diabetic complications, osteoporosis, inflammatorybowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis,xanthoma or cancer.
 32. A medicine for reducing plasma glucose,triglycerides, total cholesterol, LDL, VLDL and free fatty acids in theplasma comprising an effective amount of a polymorphic Form selectedfrom Form I to IV of 5-[4-[2-[N-methyl-N-(2-pyridyl) amino]ethoxy]benzyl] thiazolidine-2,4-dione maleate, having the formula I as definedin claims 1-4 or a pharmaceutical composition as claimed in claims 9 and10.
 33. A medicine for preventing or treating hyperlipidemia,hypercholesteremia, hyperglycemia, osteoporosis, obesity, glucoseintolerance, leptin resistance, insulin resistance, or diseases in whichinsulin resistance is the underlying pathophysiological mechanismcomprising a polymorphic Form selected from Form I to IV of5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, having the formula I as defined inclaims 1-4 or a pharmaceutical composition as claimed in claims 9 and 10and HMG CoA reductase inhibitors, fibrates, nicotinic acid,cholestyramine, colestipol or probucol.
 34. A medicine according toclaim 33, wherein the disease is type II diabetes, impaired glucosetolerance, dyslipidaemia, disorders related to Syndrome X such ashypertension, obesity, atherosclerosis, hyperlipidemia, coronary arterydisease and other cardiovascular disorders, certain renal diseasesincluding glomerulonephritis, glomeruloselerosis, nephrotic syndrome,hypertensive nephrosclerosis, retinopathy, nephropathy, disordersrelated to endothelial cell activation, psoriasis, polycystic ovariansyndrome (PCOS), useful as aldose reductase inhibitors, for improvingcognitive functions in dementia and treating diabetic complications,osteoporosis, inflammatory bowel diseases, myotonic dystrophy,pancreatitis, arteriosclerosis, xanthoma or cancer.
 35. A medicine forreducing plasma glucose, triglycerides, total cholesterol, LDL, VLDL andfree fatty acids in the plasma, which comprises a polymorphic Formselected from Form I to IV of5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dionemaleate, having the formula I as defined in claims 1-4 or apharmaceutical composition as claimed in claims 9 and 10 and HMG CoAreductase inhibitors, fibrates, nicotinic acid, cholestyramine,colestipol or probucol.